N,N-dimethyl-N&#39;-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent

ABSTRACT

N,N-dimethyl-N&#39;-phenylthiocarbamyl formamidine and its use as an anti-inflammatory agent.

This is a division of application Ser. No. 572,242, filed Apr. 28, 1975,now U.S. Pat. No. 3,959,368.

This invention relates to N,N-dimethyl-N'-phenylthiocarbamyl formamidinewhich is useful as an anti-inflammatory agent.

The compound of this invention, N,N-dimethyl-N'-phenylthiocarbamylformamidine, is novel and has the following structural formula ##STR1##

The compound of this invention can be prepared according to the teachingof the following example.

EXAMPLE N,N-Dimethyl-N'-Phenylthiocarbamyl formamidine ##STR2##

6.1 g. phenylthiourea and 4.3 g. dimethyl formamide dimethylacetal weresuspended in 100 ml. of benzene with ˜ 100 mg of p-toluene sulfuric acidand the mixture distilled through a 6 plate distilling column. Themethanol-benzene azeotrope, bp 57° C, came off rapidly. After the bprose to 80° C, the mixture was cooled and the product crystallized fromthe benzene. The yield was 6.3 g of solid m.p. 131°-138° C which wastriturated with ether to give 6 g m.p. 139°-143° C.

Hereinafter the compound of the example will be called Compound No. 1.

ANTI-INFLAMMATORY SCREENING

The compounds of the present invention have pharmaceutical activityespecially as anti-inflammatory agents. Anti-inflammatory activity isdemonstrated by a test which involves the diminution of experimentaledema induced in the hind paw of the rat by the injection ofcarrageenin.

Carrageenin injected into the foot of the rat produces an edematouscondition which simulates part of the inflammatory process.Non-steroidal anti-inflammatory compounds inhibit the formation of thisedema.

METHODS AND PROCEDURES

The procedure used for measuring the inhibition of carrageenin-inducededema is a standard procedure well-known in the pharmaceutical art andis as follows:

Male rats (Long Evans Strain) weighing between 130 - 200 grams are usedin this assay. Five rats each are used in the treatment groups and inthe known standard control; whereas ten rats are used in the controledema group. Unless otherwise indicated, phenylbutazone is administeredorally at 100 mg/kg to the standard control group. The edema controlgroup is administered the vehicle which consists of 0.25%methylcellulose solution. All of the rats are fasted for at least 15hours prior to the test. Water is available ad libitum. All of theexperimental drugs are given orally and are dissolved or suspended in0.25% methylcellulose solution. One hour after administration of thetest compound, 0.05 ml of a 1% sterile solution of carrageenin isinjected into the plantar tissues of the left hind paw of each rat.Three hours after carrageenin administration, the paw volumes ofinjected paws are then measured by means of a water displacementapparatus. The apparatus used is a modification of that described byAdamkiewicz et al., Canadian Journal of Biochemistry and Physiology, 33:332, 1955. The amount of edema is calculated and the percent reductionof edema from control values is determined. The mean volume of edema,based on 50 determinations, is 1.25 cc with a standard deviation of0.226 cc. A reduction in edema greater than 25% of the control value isconsidered significant. Based on 46 determinations, phenylbutazoneproduced a mean inhibition of edema of 43.8% with a standard deviationof 13.4%.

We have found that the compounds of this invention produce a significantinhibition of induced edema in rats at a dose rate of 200 mg/kg.

Table II shows the reduction in edema in the hind paw of the rataccording to the above-described test procedure at 200 mg/kg unlessotherwise indicated.

                  TABLE II                                                        ______________________________________                                        Percent Reduction in Edema at 200 mg/kg                                       Compound        Percent Reduction                                             Number          of Induced Edema                                              ______________________________________                                        1               56                                                            ______________________________________                                    

The compounds of the present invention, either alone or in the form ofpharmaceutical composition may be administered to an animal subject inany of a number of forms and via any of several routes. Thus, thecompounds or compositions thereof may be orally administered in the formof tablets, pills, capsules, or in the form of a suspension. Thecompounds may also be administered parenterally in the form of aninjectable solution or suspension. The compounds or compositions thereofmay also be administered topically, in the form of an ointment, orrectally, in the form of a suppository.

When orally administering the compounds or compositions, use can be madeof a tablet, pill or capsule consisting entirely of the desiredcompound, although ordinarily, a composition comprising an effectiveamount of the compound and varying amounts of one or morephysiologically inert materials such as carriers, vehicles, binders andthe like will be used. Additionally, the compounds may be orallyadministered in the form of a suspension thereof in a suitable vehiclesuch as a syrup.

When parenterally administering the compounds or compositions, use maybe made of a parenteral solution or suspension of the compound in asuitable solvent or suspension medium.

The compounds of the present invention may also be administered rectallyin the form of a suppository comprising an effective amount of thedesired compound and a suitable vehicle such as petroleum jelly.

Finally, the compounds of the present invention may be applied topicallyin the form of an ointment, salve, cream or lotion comprising aneffective amount of the desired compound and a suitable vehicle such aspetroleum jelly, etc.

We claim:
 1. A method of treatment of an inflammatory condition in amammal comprising administering to said mammal an anti-inflammatoryeffective amount of N,N-dimethyl-N'-phenylthiocarbamyl formamidine.